Pre-dried granulation and production of sublingual compressed organic nitrate tablets with selected solubilizing agents



United States Patent PRE-DRIED GRANULATION AND PRODUCTION OF SUBLINGUAL COMPRESSED ORGANIC NI- TRATE TABLETS WITH SELECTED SOLUBILIZ- ING AGENTS Fred C. Ninger, Livingston, N.J., assignor to Warner- Lambert Pharmaceutical Company, Morris Plains, N.J., a corporation of Delaware No Drawing. Filed May 27, 1959, Ser. No. 816,081

14 Claims. (Cl. 167-82) This invention relates to therapeutic agents in the form of compressed tablets for sublingual administration and relates more particularly to a new and improved form of compressed tablet for sublingual administration in the treatment of acute coronary attacks, which is capable of rapid disintegration when so administered thereby producing an extremely rapid buccal absorption of the therapeutic agent incorporated in said tablet. The present invention also relates to a method of producing said sublingual compressed tablets.

Organic nitrates, particularly pentaerythritol tetranitrate and glyceryl trinitrate, have been widely used to bring about the dilation of coronary vessels following a coronary attack. Pharmaceutical preparations comprising such organic nitrates have been available heretofore in the form of compressed tablets formed in the conventional manner by compressing a granulation of the active therapeutic agent in combination with certain inert pharmaceutical ingredients. These pharmaceutical ingredients may include any of the well-known gums as well as lubricants such as talc, stearic acid, and magnesium stearate. In addition, such inert diluents as starch, lactose, terra alba, sucrose, dextrose, sorbitol and the like are conventionally included to provide a tablet of convenient size since only a relatively small amount of active therapeutic ingredient is normally present in each tablet.

Compressed tablets of this type are commonly prepared by forming the mixed ingredients into a free flowing granulation which is then compressed into tablets of the desired size using conventional tablet forming equipment.

Tablets formed in this manner are suitable for oral administration and the disintegration of the tablet in the stomach or in the intestines makes the therapeutic agent available for absorption into the blood stream. In this manner it is carried throughout the system. Tablets which 3 are so administered may have a disintegration time of from minutes to one hour or even longer depending upon their formulation. Where release of the therapeutic agent in the stomach is not desired, an enteric coating is commonly applied to the tablets so that they Will be carried through the stomach unaltered and into the intestine. It is quite apparent, of course, that these tablets will not release their therapeutic agent for a considerable time after being ingested. In many instances, depending upon the condition treated and the therapeutic agent being employed, the disintegration time presents no problem.

Where an acute coronary attack occurs it is essential that the active therapeutic ingredient, that is the organic nitrate, be absorbed into the blood stream as rapidly as possible in order to have a prompt eflect. Sublingual administration is a desirable means of administering a preparation Where rapid absorption is desired, since the buccal absorption which follows the sublingual administration places the therapeutic ingredient into the blood stream immediately. Effective sublingual administration requires extremely rapid disintegration of the preparation with a result that an ordinary compressed tablet, such as the type just described with a disintegration time of from 10 minutes to an hour or longer, is unsuitable.

Heretofore, where rapid release of the therapeutic in- "ice gredient following sublingual administration is desired, it has been conventional to prepare the preparation in the form of a tablet triturate. Such tablet triturates are prepared by a wet molding technique which is well-known in the art. In this method the powdered ingredients which are to be formed into the tablets are wetted with an aqueous alcohol solution in an amount sulficient to produce a damp mass. The damp mass so formed is shaped by being placed in molds or dies of the desired size and the shaped mass is then gently pressed out of the mold and allowed to dry to evaporate the aqueous alcohol. It is apparent that the wet molding technique for producing tablet triturates is time consuming and in addition the finished tablets are relatively soft, do not have clear sharp outlines and are subject to crumbling on handling. In addition, satisfactory control of tablet size, weight and shape are difiicult when tablet triturates are produced by the wet molding technique.

It is an object of this invention is to prepare compressed tablets capable of rapid disintegration upon sublingual administration for use in the treatment of acute coronary attacks.

Another object of this invention is to provide an improved process for the production of compressed tablets capable of rapid disintegration upon sublingual administration.

Other objects and the advantages of this invention will become apparent from the following detailed description.

It has now been found that compressed tablets which disintegrate very rapidly when administered sublingually are obtained if the granulation comprising the active therapeutic ingredients and pharmaceutical diluents from which the tablets are compressed includes a solubilizing agent. It has also been found that compressed tablets which disintegrates rapidly sublingually may be improved in mechanical stability if a small portion of the granulation prior to tablet forming is blended with a conventional tablet forming lubricant.

The active therapeutic ingredient in the compressed tablets of this invention is an organic nitrate or mixture of organic nitrates, more particularly pentaerythritol tetranitrate alone or in combination with glyceryl trinitrate. The presence of glyceryl trinitrate in combination with pentaerythritol tetranitrate in a compressed tablet of the present invention insures extremely rapid treatment of an acute coronary attack and also several hours protection against subsequent attacks.

It is an essential feature of the present invention that the granulation from which the tablets are compressed includes a solubilizing agent. Useful solubilizing agents include theamino lower alkyl carboxcyclic acids having 2 to 6 carbon atoms, such as glycine, alanine, leucine and the like, urea and betaine salts such as betaine hydrochloride. It has been found that urea is a particularly effective solubilizing agent. The amount of solubilizing agent used may range from about 1 to about 35 percent by weight of the tablet with a range of l to 5 percent by weight being generally preferred.

In addition to the organic nitrate and the solubilizing agent, the compressed tablets of this invention contain conventional pharmaceutical diluents such as lactose, sucrose and the like. These diluents are desirable in preparing a tablet of convenient size and in addition serve to reduce the concentration of the organic nitrates during the preparation of the granulations to minimize any possible hazards which might result through handling of the organic nitrates.

In preparing the compressed tablets of this invention the ingredients are mixed in the presence of a liquid such as aqueous alcohol, the wet mixture is dried and then granulated through a' suitable sized screen. The granules are then formed into tablets in the conventional manner.

It has been found that compressed tablets may be obtained having improved mechanical stability by the incorporation of a conventional tablet forming lubricant in a portion of the granulation prior to tablet formation. Any of the conventional lubricants used in tablet formation such as the metal stearates, including calcium stearate, magnesium stearate and the like, and stearic acid may be used. In accordance with this preferred embodiment of the present invention, between about and about 15 percent by weight of the granulation comprising the organic nitrate, the solubilizing agent and the pharmaceutical diluents is blended with a lubricant of the type described above. The amount of lubricant used will normally be in the range of about 1 to about 4 percent by weight of the portion of the granulation with which it is blended. After mixing the lubricant with the portion of the granulation, this portion is regranulated and the granules blended with the remainder of the initial granulation. The mixed granulations are then formed into tablets in the conventional manner. The amount of lubricant used represents a small proportion, based on the total weight of the tablet, of the amount of lubricant conventionally used in the formation of compressed tablets. It has been found that this small quantity of lubricant improves the mechanical strength of the compressed tablet without adversely effecting the rate of dis integration of the tablet after sublingual administration.

Advantageously, the granulation may also contain a hydrophyllic colloid which is of value in aiding the disintegration of the tablet sublingually. Useful hydrophyllic colloids are guar gum, gum tragacanth, gum acacia and cellulose derivatives such as carboxymethyl cellulose and methyl cellulose. The colloids may be employed in amounts up to about 0.5 percent by weight of the compressed tablet formed.

The following examples are included further to illustrate the present invention:

Example I To parts by weight of pentaerythritol tetranitrate and 60 parts by weight of lactose (U.S.P.) containing 0.007 part by weight of D. & C. Red #7, 0.3 part by weight of glyceryl trinitrate dissolved in 3 parts by weight of ethyl alcohol are added. To this mixture are added 1.3 parts by weight of betaine hydrochloride in 3 parts by weight of water and, after mixing, about 5 parts by weight of alcohol are added to wet the resulting mass uniformly. The latter is dried at room temperature and passed through a ZO-mesh screen. The dried granulation is then compressed to form 72 mg. tablets on a high speed rotary tablet press. The sublingual disintegration of the tablets so formed is slightly less than 7 seconds.

Example II To 109.5 grams of U.S.P. lactose is added 0.008 gram of D. & C. Red #7 color and the mixture is blended thoroughly. The blended mixture is added to 700 grams of a mixture of 1 part by weight pentaerythritol tetranitrate to 6 parts by weight U.S.P. sucrose and the resulting mixture is thoroughly blended. To this mixture is slowly added a solution of 3.6 grams of glyceryl trinitrate dissolved in 46 ml. alcohol after which addition 64 ml. of alcohol is slowly added to the mixture with constant mixing. A quantity of 14.4 grams of urea is dissolved in 22 ml. water and the resulting solution is slowly added to the mixture of the other ingredients.

The thoroughly blended mass is spread in trays, dried at 40-50 C. for about 8 hours and then granulated through a Number 10 screen. The granules, weighing 828 grams, are divided into two parts, the smaller weighing 83 grams and the larger in the amount of 745 grams.

A quantity of 2 grams of stearic acid is dissolved in 44 ml. alcohol and the resultin solution is thoroughly 7:;

blended with the 83 gram portion of the initial granulation. The resulting mass is spread in trays, dried overnight at 40-50" C. and granulated through a Number 20 screen.

This granulation, weighing 85 grams, is thoroughly mixed with the larger part of the initial granulation, weighing 745 grams, and the mixture is compressed into tablets on a high speed rotary tablet press. The tablets formed each weigh 83 mg. and are %4 inch in diameter. The sublingual disintegration time of the tablets so formed is 7 seconds.

Example III 10 parts by weight of pentaerythritol tetranitrate in admixture with 65 parts by weight of lactose are further mixed with 0.6 part by weight of glyceryl trinitrate in 3 parts by weight of ethyl alcohol and 1.0 part by weight of glycine in 5 parts by weight of water is then added. 5 parts by weight of ethyl alcohol are then added to the mass, and after mixing, the latter is dried at room temperature and lightly screened through a ZO-mesh screen. The granulation obtained is then compressed to form flat-faced mg. tablets inch in diameter. The sublingual disintegration time of these tablets is less than 8 seconds.

Example IV 10 parts by weight of pentaerythritol tetranitrate mixed with 62 parts by weight of lactose are further mixed with 0.3 part by weight of glyceryl trinitrate in 3 parts by weight of ethyl alcohol and then 2.5 parts by weight of urea in 3.75 parts by weight of water and 5 parts by weight of alcohol are added. After thorough mixing, the damp mass is air-dried and lightly screened through a 20-mesh screen. The granulation obtained is compressed to form fiat-faced 75 mg. tablets inch in diameter. The sublingual disintegration time of these tablets is about 9 seconds. i

As indicated by the foregoing examples, compressed tablets prepared in accordance with the present invention have sublingual disintegration times of less than 10 seconds. Thus, rapid absorption of the active therapeutic ingredient into the blood stream is insured.

It is understood that the foregoing detailed description is given merely by way of illustration and that many variations may be made therein without departing from the spirit of my invention.

Having described my invention, what I desire to secure by Letters Patent is:

1. A rapidly disintegrating compressed tablet for sublingual administration comprising an organic nitrate selected from the group consisting of pentaerythritol tetranitrate, glyceryl trinitrate and mixtures thereof, an inert pharmaceutical diluent and about 1 to about 35 percent by weight of the tablet of a solubilizing agent selected from the group consisting of urea, betaine salts and u-amino lower alkyl carboxylic acids having 2 to 6 carbon atoms.

2. A rapidly disintegrating compressed tablet according to claim 1 wherein said organic nitrate is pentaerythritol tetranitrate.

3. A rapidly disintegrating compressed tablet according to claim 1 wherein said organic nitrate is a mixture of pentaerythritol tetranitrate and glyceryl trinitrate.

4. A rapidly disintegrating compressed tablet according to claim 2 wherein the amount of said solubilizing agent is between 1 and 5 percent by weight of the tablet.

5. A rapidly disintegrating compressed tablet according to claim 3 wherein the amount of said solubilizing agent is between 1 and 5 percent by weight of the tablet.

6. A rapidly disintegrating compressed tablet according to claim 4 wherein said solubilizing agent is urea.

7. A rapidly disintegrating compressed tablet according to claim 5 wherein said solubilizing agent is urea.

8. A rapidly disintegrating compressed tablet for sublingual administration comprising an organic nitrate selected from the group consisting of pentaerythritol tetranitrate, glyceryl trinitrate and mixtures thereof, an inert pharmaceutical diluent, about 0.05 to about 0.6 percent by weight of the tablet of a lubricant and 1 to 5 percent by weight of the tablet of a solubilizing agent selected from the group consisting of urea, betaine salts and a-amino lower alkyl carboxylic acids having 2 to 6 carbon atoms.

9. A rapidly disintegrating compressed tablet for sublingual administration comprising about 10 parts by weight of pentaerythritol tetranitrate, about 0.36 part by weight of glyceryl trinitrate, about 71 parts by weight of an inert pharmaceutical diluent, about 0.21 part by weight of stearic acid, and about 1.4 parts by weight of urea.

10. A method of producing a rapidly disintegrating sublingual tablet consisting of mixing an organic nitrate selected from the group consisting of pentaerythritol tetranitrate, glyceryl trinitrate and mixtures thereof, an inert pharmaceutical diluent and a solubilizing agent selected from the group consisting of urea, betaine salts and u-amino lower alkyl carboxylic acids having 2 to 6 carbon atoms in the presence of a volatile liquid, drying said mixture, granulating the dried mixture and compressing the granulation into tablets.

11. A method of producing a rapidly disintegrating sublingual tablet consisting of adding a solution of glyceryl trinitrate in a volatile liquid to a mixture of pentaerythritol tetranitrate and an inert pharmaceutical diluent, adding thereto an aqueous solution of a solubilizing agent selected from the group consisting of urea, betaine salts and a-amino lower alkyl carboxylic acids having 2 to 6 carbon atoms, mixing said ingredients in the presence of an additional quantity of said liquid, drying the mixture, granulating the dried mixture and compressing the granulation into tablets.

12. A method according to claim 11 wherein said liquid is an alcohol.

13. A method of producing a rapidly disintegrating sublingual tablet consisting of adding a solution of glyceryl trinltrate in a volatile liquid to a mixture of pentaerythritol tetranitrate and an inert pharmaceutical diluent, adding thereto an aqueous solution of a solubilizing agent selected from the group consisting of urea, betaine salts and a-amino lower alkyl carboxylic acids having 2 to 6 carbon atoms, mixing said ingredients in the presence of an additional quantity of said liquid, drying the mixture to form a first granulation, dividing said first granulation into a first portion constituting about 5 to about 15 percent by weight of said first granulation and a second portion constituting about to about 85 percent by weight of said first granulation, mixing said first portion with a solution of a lubricant in a volatile liquid, the quantity of said lubricant being about 1 to about 4 percent by weight of said first portion, drying the mixture, granulating the dried mixture to form a second granulation, mixing said second granulation with said second portion of the first granulation and compressing the resulting mixture into tablets.

14. A method according to claim 13 wherein said solubilizing agent is urea, said liquid is an alcohol and said lubricant is stearic acid.

References Cited in the file of this patent UNITED STATES PATENTS 2,963,402 Nalin Dec. 6, 1960 OTHER REFERENCES Neuberg: Sitzung der physikalisch-mathematischen Klasse vorm, pp. 1034-1042, July 27, 1916.

Clarkson et al.: Manufacture of Compressed Tablets, 1944, F. J. Slotsen Machine 00., pp. 5-25.

Remington Practice of Pharmacy, Martin and Cook, 1956, pp. 374-377 and 757.

Mair: J.A.P.A., Sci. ed., February 1957, pp. 131-134. 

10. A METHOD OF PRODUCING A RAPIDLY DISINTEGRATING SUBLINGUAL TABLET CONSISTING OF MIXING AN ORGANIC NITRATE SELECTED FROM THE GROUP CONSISTING OF PENTAERYTHRITOL TETRANITRATE, GLYCERYL TRINITRATE AN MIXTURES THEREOF, AN INER PHARMACEUTICAL DILUENT AND A SOLUBILIZING AGENT SELECTED FROM THE GROUP CONSISTING OF UREA, BETAINE SALTS AND A-AMINO LOWER ALKYL CARBOXYLIC ACIDS HAVING 2 TO 6 CARBON ATOMS IN THE PRESENCE OF A VOLATILE LIQUID, DRYING SAID MIXTURE, GRANULATING THE DRIED MIXTURE AND COMPRESSING THE GRANULATION INTO TABLETS. 